To explore the effect of comprehensive nursing in the application of vacuum sealing drainage (VSD) combined with continuous irrigation in the treatment of skin soft tissue defects. Methods A total of 62 patients with skin soft tissue defects admitted to our hospital from November 2021 to April 2023 were selected as the research objects. All patients were treated with VSD combined with normal saline continuous irrigation in the first stage, and skin grafting and dressing change were performed in the second stage after the growth of fresh granulation was satisfactory. They were randomly divided into control group and observation group, with 31 patients in each group. The control group was given routine nursing, and the observation group was given comprehensive nursing. The rehabilitation time, nursing effect, occurrence of common nursing problems, pain degree and nursing satisfaction were compared between the two groups. Results The growth satisfaction time and hospitalization time of new granulation tissue in the observation group were shorter th an those in the control group, the total effective rate was high er than that in the control group, the proportion of mild pain was higher than that in the control group, and the incidence of adverse reactions was lower than that in the control group (P <0.05). There was no significant difference in nursing satisfaction between the two groups (P >0.05). Conclusion The application of comprehensive nursing in patients with skin soft tissue defects receiving VSD combined with continuous irrigation is effective, which can effectively shorten the satisfaction time of fresh granulation growth, hospitalization time, reduce the incidence of adverse reactions and the degree of pain in patients, and improve patient satisfaction with care.